AEOL-10113

Gestational Diabetes Mellitus (GDM) is a prevalent metabolic disorder during pregnancy, associated with oxidative stress and inflammation at systemic and placental levels. Manganese porphyrins (MnPs) modulate redox balance and inflammation, but their therapeutic potential in diabetic pregnants remains unexplored. This study investigated the effects of water-soluble MnP [MnTE-2-PyP]⁵⁺ (BMX-010, AEOL10113) on maternal and offspring glycemic parameters and placental alterations in a diabetic pregnant rat model induced by streptozotocin. MnP treatment was initiated on gestational day 10. Diabetic rats exhibited hyperglycemia, insulin resistance, impaired gestational and fetal mass gain, elevated plasma ALT and ALP, and decreased CK levels. MnP improved gestational mass gain, glucose tolerance, and insulin sensitivity in both mother and offspring, in addition to reducing maternal ALT and ALP levels and enhancing offspring mass gain. Histological analysis revealed that diabetes increased glycogen cell and cyst areas in the placental junctional zone and reduced fetal mesenchyme/trophoblast area in the labyrinth zone; MnP partially mitigated these alterations. At the maternal-fetal interface, diabetes elevated 8-OHdG, TBARS, ROS, HIF1α, IL-6, TNF-α, and SOD1, while downregulating Sod1, GPx1/2, Vegf, Plgf, Igf1, IL-10, and SOD enzymatic activity. MnP treatment decreased HIF1α and TBARS, increased SOD activity and catalase expression, and restored IL-10 expression at transcript and protein levels. These results indicate that MnP [MnTE-2-PyP]⁵⁺ improves maternal and offspring glycemic control, placental morphology, and redox homeostasis in diabetic pregnant rats, supporting its potential as a therapeutic strategy against diabetes-induced placental dysfunction.

Mn(III) meso‐tetrakis(N‐ethylpyridinium‐2‐yl)porphyrin chloride (MnTE‐2‐PyPCl5, BMX‐010, and AEOL10113) is among the most studied superoxide dismutase (SOD) mimics and redox‐active therapeutics, being currently tested as a drug candidate in a phase II clinical trial on atopic dermatitis and itch. The thermal stability of active pharmaceutical ingredients (API) is useful for estimating the expiration date and shelf life of pharmaceutical products under various storage and handling conditions. The thermal decomposition and kinetic parameters of MnTE‐2‐PyPCl5 were determined by thermogravimetry (TG) under nonisothermal and isothermal conditions. The first thermal degradation pathway affecting Mn‐porphyrin structural integrity and, thus, activity and bioavailability was associated with loss of ethyl chloride via N‐dealkylation reaction. The thermal stability kinetics of the N‐dealkylation process leading to MnTE‐2‐PyPCl5 decomposition was investigated by using isoconversional models and artificial neural network. The new multilayer perceptron (MLP) artificial neural network approach allowed the simultaneous study of ten solid‐state kinetic models and showed that MnTE‐2‐PyPCl5 degradation is better explained by a combination of various mechanisms, with major contributions from the contraction models R1 and R2. The calculated activation energy values from isothermal and nonisothermal data were about 90 kJ mol–1 on average and agreed with one another. According to the R1 modelling of the isothermal decomposition data, the estimated shelf life value for 10% decomposition (t90%) of MnTE‐2‐PyPCl5 at 25°C was approximately 17 years, which is consistent with the high solid‐state stability of the compound. These results represent the first study on the solid‐state decomposition kinetics of Mn(III) 2‐N‐alkylpyridylporphyrins, contributing to the development of this class of redox‐active therapeutics and SOD mimics and providing supporting data to protocols on purification, handling, storage, formulation, expiration date, and general use of these compounds.